This Mentored Patient-Oriented Research Career Development Award (K23) application is designed to enable the candidate, Neelesh Nadkarni, MD, PhD, FRCPC, to become an independent investigator through the study of the influence of three major brain pathologies (amyloidosis, neurodegeneration and small-vessel disease) on the cognition-mobility interface in older adults. Dr. Nadkarni is a licensed practicing geriatricia with residency and fellowship training acquired in the United States and Canada in internal medicine, geriatric medicine, geriatric and cognitive neurology, and hospital medicine. Dr. Nadkarni also completed a PhD in medical sciences and neurosciences following completion of his clinical training. This K23 award will train Dr. Nadkarni to develop research skills in the application of advanced neuroimaging to study brain amyloidosis and neurodegeneration and enhance his knowledge of small-vessel disease imaging. It will also train him to develop the cognition-mobility interface (COMBINE) through the refinement of a protocol of dual-tasks (gait- cognition tasks). The K23 research application will test the hypothesis that amyloidosis, neurodegeneration and small-vessel disease are related to the COMBINE, which can predict impending cognitive and/or mobility decline in clinically normal older adults (defined here as those without cognitive or mobility impairment). This application is based on the premise that in clinically normal older adults, progressive functional impairment stemming from cognitive or mobility decline is a continuum that commences with deficits in cognition and/or mobility. Concurrent performance of cognitive tasks while walking assesses the COMBINE, which can serve as stress tests of the brain. Pathological age-related disease burden in brain regions important to cognitive or mobility processes, can manifest as deficits in the COMBINE in clinically normal older adults. This study will quantify amyloidosis by measuring Pittsburgh B ligand retention on Positron Emission Tomography (PET), small-vessel disease by determining volume of white matter hyperintensities on magnetic resonance imaging (MRI), and neurodegeneration by measuring fluoro-2-deoxy-glucose uptake on PET. The study will evaluate the relationships between the three pathologies affecting the COMBINE in 120 cognitively normal older adults, who will be recruited from an ongoing longitudinal study of brain amyloid deposition (RF1 AG025516; PI: Klunk). The findings from this research can provide new insights into mechanisms and clinical approaches for early detection of cognitive and mobility decline in older adults, ultimately leading to novel targets for interventions to prevent adverse outcomes of aging. This K23 training and research application involves a stellar multidisciplinary team of experts in dementia, PET and MRI neuroimaging, neuropsychology, locomotion measurement, statistics, cognitive and motor aging, postural control and geriatrics. This team of renowned leaders is committed to provide the candidate with mentorship and consultation on a regular basis through the entire duration of this award. The K23 related training and research activities will be conducted at the University of Pittsburgh which is ideally suited to undertake this work. This K23 award will ultimately enable the geriatrician-candidate to become an independent investigator conducting patient-oriented research and a leader in brain aging and the cognition-mobility interface.